1. Field of the Invention
This invention relates to lipoic acid esters of vegetable oils, their method of preparation, and their use.
2. Description of the Prior Art
Reactive oxygen, nitrogen, and sulfur species (collectively, reactive species) are understood to be likely causative agents in inflammatory and aging processes. Enzymatic and non-enzymatic antioxidants counter reactive specie generation and propagation to help preserve extra- and intracellular structures (e.g., membranes) and macromolecules (e.g., DNA, proteins) (Lü et al., Chemical and molecular mechanisms of antioxidants: Experimental approaches and model systems. J. Cell. Mol. Med. 2010, 14:840-860). Antioxidant hydro/lipophilicity dictates the extent to which an antioxidant compartmentalizes, and therefore determines which molecules are afforded protection. A variety of natural antioxidants are lipophilic (e.g., tocopherols, carotenoids) and aqueous-soluble ones can be made so (Shahidi and Zhong, Novel antioxidants in food quality preservation and health promotion. Eur. J. Lipid Sci. Technol. 2010, 112:930-940). Plant-derived phenolics are highly regarded for their antioxidant capacity. Hydroxycinnamates are a class of phenolics that are readily converted to lipophilic molecules. We recently demonstrated that a triglyceride comprised of ferulic acid and two oleic acid groups stably incorporates into model lipid membranes and provides antioxidant capacity to the membrane (Laszlo et al., Feruloyl dioleoylglycerol antioxidant capacity in phospholipid vesicles. J. Agric. Food. Chem. 2010, 58:5842-5850). To gain further insight into the effectiveness of glyceride-based antioxidants in preserving membrane components from oxidative events, a variety of lipophilic antioxidants need to be examined.
α-Lipoic acid (ALA) and dihydrolipoic acid (DHLA) are natural antioxidants in humans, and as such are the subject of intense investigation. The metabolic functions and uses of lipoic acid in disease prevention have been recently reviewed (Ghibu et al., Antioxidant properties of an endogenous thiol: Alpha-lipoic acid, useful in the prevention of cardiovascular diseases. J. Cardiovasc. Pharmacol. 2009, 54:391-398). Biewenga and colleagues summarized the pharmacology of ALA and its role in mitigating oxidative stress (Biewenga et al., The pharmacology of the antioxidant: Lipoic acid. Gen. Pharmacol. 1997, 29:315-331). Mitochondrial components are particularly sensitive to free radical damage, which can lead to lower mitochondrial performance and programmed cell death. Lipoic acid acts to prevent such damage (Palaniappan, A. R.; Dai, A., Mitochondrial ageing and the beneficial role of α-lipoic acid. Neurochem. Res. 2007, 32:1552-1558). Many patented ALA derivatives have been prepared, including polymeric forms (Packer et al., Lipoic acid analogs. U.S. Pat. No. 6,387,945, 2002; and Yu and Lee, Antioxidant polymers containing [1,2]-dithiolane moieties and uses thereof. U.S. 2010/009865 A1 2010). Koufaki and colleagues provide a comprehensive review of ALA conjugates (esters and amides) for therapeutic interventions, demonstrating the synergetic potential of covalently linked multifunctional molecules (Koufaki et al., Multifunctional lipoic acid conjugates. Curr. Med. Chem. 2009, 16:4728-4742). Many of ALA's capabilities are linked to its antioxidant capacity (Packer and Cadenas, Lipoic acid: Energy metabolism and redox regulation of transcription and cell signaling. J. Clin. Biochem. Nutr. 2011, 48:26-32). A mixture of lipoic acid and hydroxycinnamic acids was shown to be a potent antioxidant combination, with the hydroxycinnamate serving to reduce oxidized lipoic acid (Lu and Liu, Interactions of lipoic acid radical cations with vitamins c and e analogue and hydroxycinnamic acid derivatives. Arch. Biochem. Biophys. 2002, 406:78-84). Lee and colleagues prepared lipoic acid esters of polyols, including glycerol, and prepared antioxidant nanospheres (200-600 nm) from them for therapeutic uses (Lee et al., Preparation and characterization of antioxidant nanospheres from multiple α-lipoic acid-containing compounds. Bioorg. Med. Chem. Lett. 2009, 19:1678-1681). HOCl (hypochlorous acid) led to rapid consumption of the nanospheres. These spheres were shown to protect 1-antiproteinase from oxidation by HOCl (produced by halogenation of hydrogen peroxide by myeloperoxidase). HOCl can in turn generate highly reactive hydroxyl radical species that may attack polyunsaturated lipids. It was demonstrated that DHLA, but not ALA, was effective in preventing peroxidation of linoleic acid or human non-HDL fraction catalyzed by lipoxygenases (Lapenna et al., Dihydrolipoic acid inhibits 15-lipoxygenase-dependent lipid peroxidation. Free Radical Biol. Med. 2003, 35:1203-1209). DHLA was an effective scavenger of stable free radicals such as DPPH in ethanol. The mode of action for DHLA was ascribed to its ability to inactivate lipoxygenase, and possibly from scavenging fatty acid peroxyl radicals generated by the enzyme. Thus, ALA scavenges hydroxyl radicals, HOCl and singlet oxygen, while DHLA additionally provides protection against weaker oxidants. ALA and DHLA demonstrate beneficial health effects for a multiplicity of tissues and organs.
As with other major organs, skin tissues are subject to a broad array of environmental assaults (e.g., UV light, ozone), diseases, and age-related changes that result in inflammation, cosmetic alterations, and aging (Yamasaki and Gallo, The molecular pathology of rosacea. J. Dermatol. Sci. 2009, 55:77-81). It was reported that DHLA significantly inhibited the priming and activation stages of skin inflammation induced by topical 12-O-tetradecanoylphorbol-13-acetate application to mouse skin (Ho et al., Dihydrolipoic acid inhibits skin tumor promotion through anti-inflammation and anti-oxidation. Biochem. Pharmacol. 2007, 73:1786-1795). Tsuji-Naito and coworkers demonstrated that the zinc complex of an aqueous-soluble dihydrolipoic acid derivative was effective in suppressing melanin formation in skin melanocytes by combining with tyrosinase reaction products (Tsuji-Naito et al., Modulating effects of a novel skin-lightening agent, α-lipoic acid derivative, on melanin production by the formation of dopa conjugate products. Bioorg. Med. Chem. 2007, 15:1967-1975). Mouse fibroblasts exposed to ALA had lower expressed matrix metalloproteinase-2 activity, indicating a positive dermal influence would be expected with the antioxidant (Voronkina et al., Activity of matrix metalloproteinases in normal and transformed mouse fibroblasts exposed to antioxidants. Cell Tissue Biol. 2009, 3:56-60). Topical treatments with antioxidants such as ALA derivatives are anticipated to have an anti-aging influence on skin (Han and Nimni, Transdermal delivery of amino acids and antioxidants enhance collagen synthesis: In vivo and in vitro studies. Connect. Tissue Res. 2005, 46:251-257; and Herschthal and Kaufman, Cutaneous aging: A review of the process and topical therapies. Expert Rev. Dermatol. 2007, 2:753-761).
Topical delivery of active agents may avoid the metabolic modification issues associated with oral administration and non-target organ influences (Bhatti et al., Mechanisms of antioxidant and pro-oxidant effects of α-lipoic acid in the diabetic and nondiabetic kidney. Kidney Int. 2005, 67:1371-1380; and Hsieh et al., Quercetin and ferulic acid aggravate renal carcinoma in long-term diabetic victims. J. Agric. Food. Chem. 2010, 58:9273-9280). Liposomal vesicles can serve as cutaneous delivery vehicles for antioxidants or as stabilized carriers of oxidation sensitive cosmeceuticals (medicinal cosmetics) and drugs (El Maghraby et al., Liposomes and skin: From drug delivery to model membranes. Eur. J. Pharm Sci. 2008, 34:203-22). Clinical trials determined that application of ALA-containing cream diminishes facial skin photoaging (Beitner, Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% α-lipoic acid related to photoageing of facial skin. British Journal of Dermatology 2003, 149:841-849). Unformulated ALA barely penetrates the skin's stratum corneum layer (Podda et al., Kinetic study of cutaneous and subcutaneous distribution following topical application of [7, 8-14c]rac-[alpha]-lipoic acid onto hairless mice. Biochem. Pharmacol. 1996, 52:627-633). Water-based, easy-to-use formulations have been prepared using surfactants with nanoparticulate ALA (Ruktanonchai et al., Physicochemical characteristics, cytotoxicity, and antioxidant activity of three lipid nanoparticulate formulations of alpha-lipoic acid. AAPS PharmSciTech 2009, 10:227-234) or water-in-oil ALA emulsions supplemented with skin penetration enhancers (Richert et al., Transdermal delivery of two antioxidants from different cosmetic formulations. Int. J. Cosmetic Sci. 2003, 25:5-13).
However, despite these and other advances, the need remains for improved lipoic acid agents and methods for their production.